Today, antibodies are widely used agents in the field of medicine and research. In medicine, they find application in many different fields. For example, antibodies are used as labeling agents for detecting certain markers which allow the diagnosis and/or prognosis of diseases or the determination of specific body parameters such as, for example, the presence or concentration of certain hormones.
Furthermore, antibodies are also used as therapeutic agents in the treatment and prophylaxis of a variety of diseases such as cancer, cardiovascular diseases, inflammatory diseases, macular degeneration, transplant rejection, multiple sclerosis, and viral infections. In these therapies, the antibody may possess therapeutic activity on it own, for example by blocking receptors or messenger molecules, thereby inhibiting their disease-relevant functions, or by recruiting and activating components of the patient's immune system. Alternatively, the antibody may be coupled to another agent having therapeutic activity. In particular in the treatment of cancer and infections, said further agent has cell-killing activity and may be, for example a radioisotope or a cytotoxin. In another application, antibodies may be used to passively immunize a patient by transferring suitable antibodies into the patient's circulation.
A critical aspect of the in vivo application of antibodies, in particular of their therapeutic use, is the time the antibodies remain in the patient's body, i.e. the circulation half-life of the antibodies.
Many approaches to increase the circulation half-life of proteins involve artificial modifications of the proteins such as conjugating them with other molecules which increase the half-life or fusing them to other half-life-increasing proteins or peptides. However, these approaches involve certain disadvantages. They normally involve complicated production processes and there are frequently problems with their biocompatibility or pharmaceutical approval. Moreover, these modifications often are detrimental to the biological activities of the antibodies, in particular their antigen binding properties and their downstream signaling such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Furthermore, with respect to glycoproteins such as FSH in some cases the amount of sialic acids attached to the carbohydrate chains of the glycoproteins influences the clearance rate and thus, the circulation half-life of the glycoprotein. However, according to the state of the art this principle cannot be attributed to antibodies. First, a high degree of sialylation of the carbohydrate chain attached to the Fc region of an IgG antibody negatively affects the biological activities of the antibody. In particular, the ADCC of the antibody is greatly reduced due to a decreased affinity of the Fc region to the respective Fc receptor (see, e.g., Scallon, B. J. et al. (2006) Molecular Immunology 44, 1524-1534). Furthermore, the degree of sialylation of carbohydrate chains attached to glycosylation sites in the Fab region is considered to have no impact on the circulation half-life of the antibody but rather influences antigen binding (see, e.g., Huang, L. et al. (2006) Analytical Biochemistry 349, 197-207, Millward, T. A. et al. (2008) Biologicals 36, 41-47, Jefferis, R. (2009) Methods in Molecular Biology 483, 223-238, and Sold, R. J. et al. (2010) Biodrugs 24, 9-21).
On the other hand, also antibodies having a low circulation half-life are important for some applications. For example, for diagnostic purposes using radioactive imaging methods, antibodies conjugated to radionuclides are used. Since the imaging procedure can be performed in a relatively short time and the radionuclides conjugated to the antibodies have certain adverse side effects, a fast clearance of the conjugate from the patient's circulation is advantageous.
Therefore, there is a need in the art to regulate, in particular to increase or decrease the circulation half-life of antibodies, in particular therapeutically or diagnostically useful antibodies, without using chemical conjugates or fusion proteins.